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Phase I and Biological Studies of DB67 - A Blood Stable Camptothecin

DB67（一种血液稳定性喜树碱）的 I 期和生物学研究

基本信息

批准号：
7344745
负责人：
Markos Leggas
金额：
$ 20.51万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-26 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7344745
关键词：
Adult Affinity Applications Grants Biological Biological Models Blood Blood Circulation Camptothecin Camptothecin Analogue Cells Charge Class Clinical Clinical Research Clinical Trials Colon Daily Data Development Diffuse Dose-Limiting Drug Formulations Drug Kinetics Engineering Enzymes Generations Genetic Polymorphism Genus Cola Glioma Goals Human Hydrolysis In Vitro Intravenous Lactones Lipid Bilayers Liver Maximum Tolerated Dose Mediating Modeling Molecular Molecular Target Noma Outcome Patients Personal Satisfaction Pharmaceutical Preparations Pharmacogenetics Phase Phase I Clinical Trials Plasma Pre-Clinical Model Property Proteins Rapid Access to Intervention Development Recurrence Recurrent Malignant Neoplasm Refractory Serum Albumin Solid Neoplasm Standards of Weights and Measures Structure Structure-Activity Relationship Therapeutic Topotecan Toxic effect Toxicology United States Food and Drug Administration Water Xenograft Model Xenograft procedure analog aqueous base carboxylate cytotoxic day drug metabolism experience improved in vivo intravenous administration irinotecan lipophilicity melanoma programs tumor uptake

项目摘要

As a class, the camptothecins have been widely recognized for their therapeutic potential, which for many reasons, including the instability of the lipophilic lactone moiety, has not been fully realized. DB-67 (7-t- butyldimethylsilyl-10-hydroxycamptothecin) is a third generation analog that was engineered to be blood stable and highly potent, on the basis of structure-activity relationship studies. The camptothecins have a labile a-hydroxy-5-lactone ring, which hydrolyzes to yield the negatively charged carboxylate form. Compared to the uncharged lactone, the negatively charged carboxylate is less likely to diffuse into cells and is often considered "inactive." Based on its blood stability and anti-tumor activity, DB-67 was selected by the NCI for development through three cycles of the RAID program. Data from NCI studies and from collaborative efforts revealed impressive in vitro and in vivo anti-tumor activity, particularly in glioma models, but also in melanoma and colon xenograft models. Currently DB-67 formulation and toxicology studies have been completed and clinical grade material is available through the NCI. Based on the extensive formulation, toxicology, and pharmacokinetic profile observed in preclinical models, and its potential to exert a potent anti-tumor effect in humans, we hypothesize that DB-67 will be well-tolerated and efficacious in clinical trials. This grant application outlines the clinical studies and the correlative pharmacokinetic studies that will define DB-67 disposition and toxicity in patients with refractory solid tumors. The following specific aims will be accomplished: 1.1) To estimate the maximum tolerated dose (MTD) and describe the dose limiting toxicities (DLT) of intravenous DB-67 administered once daily for 5 days every 21 days to adults with recurrent or refractory solid tumors in which standard therapies are not effective; 1.2) To characterize the plasma pharmacokinetics of DB-67 and metabolites after intravenous administration and relate DB-67 pharmacokinetics and toxicity. Ultimately, the objective is to use DB-67 as a single agent or in combination with other molecular-targeted therapies or cytotoxics in frontline therapy with the goal to improve overall patient outcome.

作为一类，喜树碱因其治疗潜力而被广泛认识，这对许多人来说原因，包括亲脂性内酯部分的不稳定性，还没有完全了解。DB-67(7-t- 丁基二甲基硅基-10-羟基喜树碱)是第三代类似物，它被设计成血液在构效关系研究的基础上，稳定性和高效性。喜树碱有一种不稳定的α-羟基-5-内酯环，可水解生成带负电荷的羧酸盐。与不带电荷的内酯相比，带负电荷的羧酸盐不太可能扩散到细胞和通常被认为是“不活跃的”。基于其血液稳定性和抗肿瘤活性，DB-67被选为 NCI通过三个周期的RAID计划进行开发。来自NCI研究和来自合作努力显示出令人印象深刻的体外和体内抗肿瘤活性，特别是在胶质瘤模型中，而且在黑色素瘤和结肠异种移植模型中也是如此。目前，DB-67的配方和毒理学研究已经完成，临床级别的材料可以通过NCI获得。基于广泛的提法，在临床前模型中观察到的毒理学和药代动力学特征，以及它对在人类的抗肿瘤作用方面，我们假设DB-67在临床试验中耐受性良好和有效。这项资助申请概述了临床研究和相关的药代动力学研究，这些研究将定义 DB-67在难治性实体瘤患者中的处置和毒性。以下是具体目标完成：1.1)估计最大耐受量(MTD)并描述剂量限制毒性 (DLT)静脉注射DB-67，每天一次，每21天连续5天，用于复发或标准治疗无效的难治性实体肿瘤；1.2)确定血浆的特征 DB-67及其代谢物静脉给药后的药代动力学药代动力学和毒性。最终，目标是将DB-67用作单一药剂或组合使用在一线治疗中使用其他分子靶向治疗或细胞毒性药物，目标是改善整体病人结局。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacokinetic modeling of the blood-stable camptothecin analog AR-67 in two different formulations.

两种不同制剂中血液稳定性喜树碱类似物 AR-67 的药代动力学模型。

DOI：
10.1002/bdd.2199
发表时间：
2019
期刊：
Biopharmaceutics & drug disposition
影响因子：
2.1
作者：
Liu,Xiaoxi;Adane,Eyob;Tang,Fei;Leggas,Markos
通讯作者：
Leggas,Markos

A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies.

DOI：
10.1158/1078-0432.ccr-09-2429
发表时间：
2010-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Arnold SM;Rinehart JJ;Tsakalozou E;Eckardt JR;Fields SZ;Shelton BJ;DeSimone PA;Kee BK;Moscow JA;Leggas M
通讯作者：
Leggas M

The effect of breast cancer resistance protein, multidrug resistant protein 1, and organic anion-transporting polypeptide 1B3 on the antitumor efficacy of the lipophilic camptothecin 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in vitro.

乳腺癌耐药蛋白、多药耐药蛋白1和有机阴离子转运多肽1B3对亲脂性喜树碱7-叔丁基二甲基甲硅烷基-10-羟基喜树碱（AR-67）体外抗肿瘤功效的影响。

DOI：
10.1124/dmd.112.050021
发表时间：
2013
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
0
作者：
Tsakalozou,Eleftheria;Adane,EyobD;Kuo,Kuei-Ling;Daily,Abigail;Moscow,JeffreyA;Leggas,Markos
通讯作者：
Leggas,Markos

Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.

在非小细胞肺癌异种移植物和人类中延长亲脂性喜树碱类似物 AR-67 的给药。